5-aroyl-2-(beta-r3-ethyl)-1-loweralkyl-pyrroles

ABSTRACT

COMPOUNDS OF THE CLASS OF 5-AROYL-2-(B-R3-ETHYL)-1LOWERALKYL-PYRROLES USEFUL AS ANTI-INFLAMMATORY AGENTS, SAID R3 BEING VARIOUS AMINO AND AMIDO FUNCTIONS.

United States Patent Office 3,707,478

Patented Dec. 26, 1972 which acetamides are also described in the aforementioned 3,707,478 application Ser. No. 5,958. The acetamido function of the S'AROYL'2'U3'R3'ETHYL)'I'LOWERALKYL' Formula II-a compounds is readily transformed into a PYRRQLES nitrile function by standard dehydration procedures, such John Robert q l asslgnor to 5 as, for example, by treatment with tosyl chloride in pyri- McNe'l Laboratones dine or with hos horous ox chloride No Drawing. Filed June 15, 1970, Ser. No. 46,522 P P Y Int. Cl. 226 loweralkyl loweralkyl US. Cl. 260326.3 9 Claims R, HOH R1 J; 10 Ar-CO N H-CONHz Ar-CO H-CN ABSTRACT OF THE DISCLOSURE Compounds of the class of 5-aroyl-2-(B-R -ethyl)-1- R 1% loweralkyl-pyrroles useful as anti-inflammatory agents,

The Formula I compounds, wherein R is acetamido, said R being various amino and amido functions.

are prepared by the catalytic hydrogenation of the nitriles (II) in the presence of acetic anhydride, the catalyst being a noble metal or, preferably, Raney nickel. Alkaline or DESCRIPTION OF THE INVENTION acidic hydrolysis of the thus-obtained 5-aroyl-2-(B-acet- This invention relates to novel aroyl-substituted pyry y 'py affords the roles, and, more particularly, to 5-aroyl-2(,B-R -ethyl)- 2 coffesponding 2-(fi-aminoethyl)derivatives The late l-loweralkyl-pyrroles of the formul ter in turn may be transformed into the corresponding R2 Z-(fi-dimcthylaminoethyl) derivatives (V) of Formula I by methylation of the amino function. Such methylation H 1'2, can be readily accomplished by catalytically hydrogenating r a mixture of (IV) with formalin in the presence of so- CH dium acetate and ethanol. The Z-(fl-aminoethyl) derival tives (IV) may also be prepared directly from the nitriles (I) (II) by catalytic reduction techniques, for example, by wherein R is lower alkyl, preferably methyl; R and R treating (II) with hydrogen and Raney nickel catalyst in are each a member selected from the group consisting of a lower alkanol, preferably absolute alcohol, in the preshydrogen and lower alkyl; R is a member selected from ence of ammonia. Substitution of a loweralkylamine or a the group consisting of amino, loweralkylamino, di-lowerdi-loweralkyl-amine for ammonia affords the correspondalkyl-amino and acetamido; and Ar is a member selected ing compounds of Formula I wherein R is loweralkylfrom the group consisting of phenyl and phenyl substiamino or di-loweralkyl-amino, respectively (VI).The foretuted with one or more members selected from the group consisting of chloro, fluoro, lower alkyl, lower alkoxy and trifiuoromethyl. The 5-aroyl-2-(a-R -fi-R -ethyD-4-R -1- going reactions may be illustrated by the following diagrammatic sequence:

loweralkyl-pyrroles of Formula I may also be denoted as 5-(1-R -2-R -ethyl)-4-R l-loweralkyl-pyrrol 2 yl aryl H HdNi I-I, R2

ketones (aryl=Ar). The therapeutically active acid addi- 40 tion salts of the Formula I compounds containing a basic Ar 0 N J30 ON (CHSCOM) Ar O H CH1 NHCOOH nitrogen atom are also included within the scope of this k invention.

I As used herein, lower alkyl and lower alkoxy may (I (HI) be straight or branch chained saturated hydrocarbons hav- HQ/Ni l Et H/NH2R EtOHAm/Ni l HOmNaOH or H01) ing from 1 to about 5 carbon atoms, such as, for example, HNRR methyl, ethyl, propyl, isoproyl, butyl, pentyl and the like R2 R2 alkyls, and, respectively, the corresponding alkoxys, such as methoxy, ethoxy, propoxy, isopropoxy, etc. E R1 The subject compounds (I) are obtained from the cor- ArG JJH-GHz-NHR Ar--C dH-CHr-NH; responding nitriles having the formula: N R (or --NRR) t v1 (IV) 0 R lav-bl JH-CN r5 lNaogl iiion (H) 0. R CH wherein the symbols R, R R and Ar are as previously a described. Such nitriles of Formula II, wherein R is hy- N drogen, are described in my copending US. patent application Ser. No. 5,958, filed Jan. 26, 1970. Those nitriles (v) of Formula II, wherein R is lower alkyl, may be prepared from the corresponding 5-aroyl-a-R -1,4-di-loweralkyl- The subject compounds (I) possess anti-inflammatory pyrrole-Z-acetamides of the formula: activity as demonstrated in the standard kaolin-induced rat paw edema test or cotton pellet granuloma test (both lowemlkyl tests are described in the previously mentioned applica- Rl tion Ser. No. 5,958) at doses generally ranging from O N/ about 5 to about 100 mg./ kg. body weight. For example,

with 2-(fi-acetamidoethyl-S-(p-chlorobenzoyl)-1-methyll pyrrole, 2-aminoethyl-5-(p-toluoyl)-1-methylpyrrole hy- (II-a) drcohloride and Z-(B-dimethylaminoethyl)-5-p-toluoyl-1- 3 methylpyrrole hydrochloride, an inhibition of 22%, 75% and 32%, respectively, is observed in the kaolin-induced rat paw edema assay at respective dosages of 50, 25 and 25 mg./kg. body weight.

Due to the available a-carbon atom (when R equals lower alkyl) present in the subject compounds (I), it is evident that their existence in the form of stereochemical isomers (enantiomorphs) is possible. Thus by standard methods of resolution the corresponding or forms of the desired compounds will be obtained. Such pharmacologically active enantiomorphs are naturally intended to be included within the scope of this invention.

The therapeutically active non-toxic acid addition salts of the basic nitrogen-containing compounds of Formula I are prepared by treatment with an appropriate acid such as an inorganic acid, e.g., hydrochloric, hydrobromic, hydriodic, sulfuric, nitric and the like acids; or an organic acid such as acetic, propionic, glycolic, lactic, pyruvic, malonic, maleic, malic, succinic, fumaric, tataric, citric, benzoic, cinnamic, methane sulfonic, salicyclic and the like acids.

The following examples are intended to illustrate, but not to limit, the scope of the present invention.

Example I ll CI-Q-C-GCmoHZNHC on- N I 2 (,8 acetamidoethyl) (p chlorobenzoyl) 1- methy1pyrrole.-A solution of 5.5 g. (0.02 mole) 5-pchlorobenzoyl) 1 methylpyrrole 2 acetonitrile and 75 ml. of acetic anhydride is hydrogenated in a Parr shaker over Raney nickel catalyst. An initial pressure of thirty pounds per square inch of hydrogen is employed. The catalyst is filtered off. The solvent is evaporated resulting in about 3.8 g. of a yellow solid, Z-(fi-acetamidoethyl)-5-(p-chlorobenzoyl)-1-methylpyrrole, which is purified by recrystallizing twice in ethyl acetate; M.P. 166l68 C.

Analysis.-Calcd. for C16H17C1N2O2 (percent): C, 63.05; H, 5.62; N, 9.19. Found (percent): C, 62.86; H, 5.63; N, 9.03.

Example II Z-(fl-acetamidoethyl) 5 (p-toluoyl) 1 methylpyrrole.A solution of 8.4 g. (0.035 mole) of l-rnethyl-S-ptoluoyl pyrrole-2-acetonitrile in approximately 100 ml. acetic anhydride is hydrogenated under 40 p.s.i. hydrogen in a Parr shaker for 18 hours over Raney nickel as the catalyst. The catalyst is then removed by filtration. The filtrate is evaporated and the resultant white solid, 2-(B- acetamidoethyl)-5-(p-toluoyl)-1-metyhlpyrrole, is purified by recrystallization in ethyl acetate; M.P. 6-159 C.

Example III The procedure of Example II may be followed to prepare the 2-(a-R -fl-acetamido-ethyl) derivatives of Formula I by using the appropriate nitrile precursor (II). For example, by substituting an equivalent quantity of the following nitriles:

5-benzoyl-l-methylpyrrole-2-acetonitrile,

5-(2',4-dichlorobenzoyl)-l-methylpyrrole-Z-acetonitrile,

5- (3'-chloro-p-toluoyl) l -methylpyrrole-2-acetonitrile,

5-(plitrifluoromethylbenzoyl)-1-methylpyrrole-2-acetonitr' e,

5- (p-methoxybenzoyl)-l-ethylpyrrole-2-acetonitrile,

5-benzoyl-l-ethyl-a-methylpyrrole-2-acet0nitrile, and

5-(p-toluoyl)-a-ethyl-1-methylpyrrole-2-acetonitrile,

for the nitrile precursor used in Example II, the following pyrroles of Formula I are obtained as respective products:

2-(fl-acetamidoethyl)-5-benzoyl-l-methylpyrrole,

2- ,S-acetamidoethyl -5-( 2,4'-dichlorobenzoyl) l-methylpyrrole,

Z-(fl-acetamidoethyl) -5- 3'-chloro-p-toluoy1) l-methylpyrrole,

2- ,B-acetamidoethyl) -5- (p-trifiuoromethylbenzoyD- lmethylpyrrole,

2- (fl-acetamidoethyl) -5- (p-methoxybenzoyl) -1-ethylpyrrole,

2- B-acetamidoethyl -5-benzoyll-ethyl-a-methylpyrrole,

and

2 (fi-acetamidoethyl -5- p-toluoyl) -a-ethyll-methylpyrrole.

Example IV Z-aminoeth'yl-S-(p-toluoyl)-l-methylpyrrole and its hydrochloride salt.-A slurry of 11.9 g.) 0.05 mole) of 1- methyl-S-(p-toluoyl)-pyrrole-2-acetonitrile in 400 ml. absolute ethanol is cooled to 0 C. with an ice-bath. Ammonia gas is bubbled through vigorously for fifteen minutes. Raney Active Nickel Catalyst No .28 (W. R. Grace & Co.) is washed three times with ethanol and introduced to the above suspension. The mixture is placed under 38 p.s.i. hydrogen and hydrogenated for 18 hours in a Parr shaker. The catalyst is then removed by filtration and the filtrate is evaporated to yield Z-aminoethyl-S-(pto1uoyl)-1-methylpyrrole as an off-white solid, M.P. 57.5-60.5 C.

The hydrochloride salt is made by dissolving the amine base in isopropanol and treating the solution with ethereal hydrogen chloride. The resultant precipitate is separated by filtration; M.P. 2172l8 C.

The hydrochloride is also prepared by treating an aqueous solution of the amine base with concentrated hydrochloric acid. It is separated by filtration and purified by recrystallization in isopropanol; M.P. 218-220 C.

Analysis.-Calcd. for C I-I ClNO (percent): C, 64.62; H, 6.86; N, 10.04. Found (percent): C, 64.61; H, 6.98; N, 10.02.

Example V The procedure of Example IV may be followed to prepare the Z-(a-R -p-amino-ethyl) derivatives of Formula I by using the appropriate nitrile precursor (II). For example, by substituting an equivalent quantity of the following nitriles:

5-(p-fluorobenzoyl)-1-methylpyrrole-Z-acetonitrile,

5-(p-ethylbenzoyl)-1-methylpyrroIe-Z-acetonitrile,

5- 3 ,4'-dimethylbenzoyl -1-methylpyrrole-Z-acetonitrile,

S-(p-chlorobenzoyl)-1,a-dimethylpyrrole-Z-acetonitrile,

5-(p-methylbenzoyl)- ot-ethyl- 1 -methylpyrrole-2-acetonitrile,

S-benzoyl-1-ethylpyrrole-Z-acetonitrile,

S-(p-methoxybenzoyl) -1-ethylpyrrole-Z-acetonitrile,

5- (p-fluorobenzoyl )-u-ethyll-methylpyrrole-Z-acetonitrile,

5- p-trifluoromethylbenzoyl) l-methylpyrrole-Z-acetonitrile, and

5-(2',4-dichlorobenzoyl)-1-n-butyl-a-methyl-pyrrole-Z- acetonitrile,

for the nitrile precursor used in Example I, the following pyrroles of Formula I and hydrochloride salt thereof are obtained as respective products:

Z-aminoethyl-S- (p-fluorobenzoyl)-l-methylpyrrole, 2-aminoethyl-5- (p-ethylbenzoyl)-l-methylpyrrole, 2-aminoethyl-5- 3 ',4'-dimethylbenzoyl)-1-methylpyrrole, Z-aminoethyl-S-(p-chlorobenzoyl)-1,a-dimethylpyrrole, 2-aminoethyl-5-(p-rnethylbenzoyl)-u-ethyl-l-methylpyrrole, 2-aminoethyl-5-benzoyl-l-ethylpyrrole, Z-aminoethyl-S-(p-methoxybenzoyl)-l-ethylpyrrole, Z-aminoethyl-S-(p-fluorobenzoyD-a-ethyl-l-methylpyrrole, I 2-aminoethyl-5- (p-trifluoromethylbenzoyl)-1-methylpyrrole, and 2-aminoethyl-5-(2',4dichlorobenzoyl)-1-n-butyl-- methylpyrrole.

Example VI (Z-dimethylaminoethyl)-1-methylpyrrol-2-yl p-tolyl ketone and its hydrochloride salt.-A solution of 4.0 g. (0.0165 mole) 5-(Z-aminoethyl)-1-methylpyrrol-2-yl ptolyl ketone in 20 ml. 95% ethanol is treated with 2.7 ml. (0.033 mole) 37% formalin. Sodium acetate (0.165 g.) and 'Raney nickel catalyst are added and the mixture is hydrogenated in a Parr Shaker for eighteen hours under 40 p.s.i. hydrogen. The catalyst is then removed by filtration and the filtrate evaporated. The residue, 5- (2 dimethylaminoethyl)-1-methylpyrrol-2-yl p-tolyl ketone, is dissolved in ethanol and converted to the hydrochloride salt by treatment with ethereal hydrogen chloride. The white precipitate, 5-(2-dimethylaminoethyl)-lmethylpyrrol-Z-yl p-tolyl ketone hydrochloride, is separated by filtration and purified by recrystallization in 2- propanol, M.P. 225227 C.

Example VII The methylation procedure of Example VI may be followed to prepare the 2-(a-R -fl-dimethylamino-ethyl) derivatives of Formula I by using the appropriate corresponding 2-(a-R -fl-amino-ethyl) precursor. For example, by substituting an equivalent quantity of each of the products obtained in Example V for the 5-(2-aminoethyl)-lmethylpyrrol-2-yl p-tolyl ketone employed in Example VI, the following pyrroles of Formula I and hydrochloride salt thereof are obtained as respective products:

Z-dimethylaminoethyl-S- (p-fluorobenzoyl) -1- methylpyrrole,

2- dimethylaminoethyl-S- (p-ethylbenzoyl)-1- methylpyrrole,

Z-dimethylaminoethyl-S- 3 ',4'-dimethylbenzoyl)-1- methylpyrrole,

Z-dimethylaminoethyl-S- (p-chlorobenzoyl)-1-adimethylpyrrole,

2- dimethylamino ethyl-S- (p-methylbenzoyl -a-ethyll-methylpyrrole,

Z-dimethylaminoethyl-S-benzoyll-ethylpyrrole,

Z-dimethylaminoethyl-S- (p-methoxybenzoyl) -1- ethylpyrrole,

Z-dimethylaminoethyl-S- (p-fiuorobenzoyl -a-ethyll-methylpyrrole,

2- dimethylaminoethyl-S- (p-trifiuoromethylbenzoyl) 1- methylpyrrole, and

Z-dimethylaminoethyl-S-(2',4'-dichlorobenzoyl)-1-nbutylrat-methylpyrrole.

Example VIII 5-(p-chlorobenzoyD-1,4-dimethylpyrrole 2 acetonitrile.-A 2.09 g. sample of p-toluene-sulfonyl chloride (0.011 mole) is added to a suspension of 2.90 g. (0.01 mole) of 5-(p-chlorobenzoyl)-l,4-dimethylpyrrole-2-acetamide in ml. of pyridine. The mixture is stirred for two hours and poured into water. The mixture is extracted with ether. The ether extract is washed with dilute HCl and brine and dried (MgSO The solvent is evaporated in vacuo and the residue is recrystallized from 2-propanol to give 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetonitrile as a crystalline solid.

Example IX (.A) By repeating the procedures of Examples II and IV, except that an equivalent quantity of S-(p-chlorobenzoy1)-1,4-dimethylpyrrole-2-acetonitrile is employed as the starting nirtile, there are obtained as respective products: 2-(flacetamidoethyl)-5-(p-chlorobenzoyl)-1,4- dimethylpyrrole and 2-aminoethyl-5-(p-chlorobenzoyl)- 1,4-dimethy1pyrrole, including the hydrochloride salt of the latter.

(B) By substituting an equivalent quantity of 2-aminoethyl-S-(p-chlorobenzoyl) 1,4 dirnethylpyrrole in the methylation procedure of Example VI, the corresponding Z-(fi-dimethylamihoethyl) 5 (p-chlorobenzoyl )-1,4-dimethylpyrrole and its hydrochloride salt are obtained.

Example X The procedure of Example VIII may be followed to transform the acetamido function of the Formula II-a compounds into the nitrile function of the corresponding Formula II compounds. For example, the following respective nitriles of Formula II are obtained by substituting an equivalent amount of the appropriate 5-aroyl-a- R -1,4-di-loweralkylpyrrole-Z-acetamide as the starting material in the procedure of Example VIII:

5- (p-toluoyl) -1 ,4-dimethylpyrrole-2-acetonitrile;

5 3 ',4'-dimethoxybenzoyl) -1,4-dimethylpyrrole-2- acetonitrile;

5- p-trifiuoromethylbenzoyl) 1,4-dimethylpyrro1e-2- acetonitrile;

5-(p-chlorobenzoyl)-4-ethyl-1-methylpyrrole-2- acetonitrile;

5- (p-chlorobenzoyl) l ,4,a-trimethylpyrrole-2- acetonitrile S-benzoyl-1,4,u-trimethylpyrrole-2-acetonitrile;

S- p-ethoxybenzoyl) l,4,u-trimethylpyrrole-2- acetonitrile;

5- (2',4-dimethoxybenzoyl)-1,4,a-trimethylpyrrole-2- acetonitrile;

5- (p-chlorobenzoyl) -4-ethyll ,a-dimethylpyrrole-2- acetonitrile; and

5- (p-chlorobenzoyl) -1 ,4-dimethy1- u-n-propylpyrrole- 2-acetonitrile.

Example XI (A) By repeating the procedures of Examples II and IV, except that an equivalent quantity of each of the Formula II nitriles obtained in Example X are employed as the starting nitrile, there are obtained, as respective products, the corresponding 2-(fi-acetamidoethyl) and 2- aminoethyl derivatives of Formula I, including the hydrochloride salts of such Z-aminoethyl derivatives.

(B) By substituting an equivalent quantity of each of the 2-aminoethyl derivatives obtained in 'Example XI-A in the methylation procedure of Example VI, the corresponding Z-(fl-dimethylaminoethyl) derivatives of Formula I and the hydrochloride salt thereof are obtained.

I claim:

1. A member selected from the group consisting of a 5-aroyl-2-(a-R -p-R -ethyl)-4-R -1-loweralkyl-pyrrole of the formula:

1 (EH-CHz-Rg wherein 'R is lower alkyl, R and R are each a member selected from the group consisting of phenyl and phenyl alkyl; R is a member selected from the group consisting of amino, di-loweralkyl-amino and acetamido; and Ar is a member selected from the group consisting of phenyl and phenyl substituted with one or two members selected from the group consisting of chloro, fiuoro, lower alkyl, lower alkoxy and trifiuoromethyl; and the therapeutically active acid addition salts of the foregoing pyrroles containing a basic nitrogen, said lower" being from 1 to 5 carbon atoms.

2. A member selected from the group consisting of a 5-aroyl-2-(a-R -[i-R -ethyl)-1-methylpyrrole of the formula:

Ar-E N wherein R and R are each a member selected from the group consisting of hydrogen and lower alkyl; R, is a member selected from the group consisting of amino, diloweralkyl-amino and acetamido; and Ar is a member selected from the group consisting of phenyl and phenyl substituted with one or two members selected from the group consisting of chloro, fluoro, lower alkyl, lower alkoxy and trifiuoromethyl; and the therapeutically active acid addition salts of the foregoing pyrroles containing a basic nitrogen, said lower being from 1 to 5 carbon atoms.

3. 2 (fi-acetamidoethyD-S-(p-ch1orobenzoyl)-l-methylpyrrole.

4. 2-(fl-acetamidoethyD-S-(p-toluoyl)-1-methylpyrrole.

5. A member selected from the group conssiting of 2-aminoethyl-5-(p-toluoyl)-1-methylpyrrole and its hydrochloride salt.

6. A member selected from the group consisting of 2-(,8 dimethylaminoethyD-S- (p-toluoyl)-1-methylpyrrole and its hydrochloride salt.

7. 2- (fl-acetamidoethyl)-5-(p-chlorobenzoyl) 1,4 dimethylpyrrole.

8. A member selected from the group consisting of 2-aminoethy1-5-(p-chlorobenzoyl) 1,4 dimethylpyrrole and its hydrochloride salt.

9. A member selected from the group consisting of Z-(B-dimethylaminoethyl) 5 (p-chlorobenzoyl)-1,4-dimethylpyrrole and its hydrochloride salt.

References Cited UNITED STATES PATENTS 3,591,602 7/1971 Lockhart 260-3263 ALTON D. ROLLINS, Primary Examiner J. A. NARCAVAGE, Assistant Examiner US. Cl. XsR. 

